Editors' ChoiceCancer

Activating β-Catenin with NCAM

Science Signaling  26 Jul 2011:
Vol. 4, Issue 183, pp. ec205
DOI: 10.1126/scisignal.4183ec205

Three main forms of neural cell adhesion molecule (NCAM) arise by alternative splicing and differ in the presence and length (NCAM140, short intracellular domain; NCAM180, long intracellular domain) or the absence of the cytoplasmic domain (NCAM120, a glycophosphatidylinositol-anchored protein). Previous work indicated that NCAM contributes to the metastasis of some cancers, including melanoma. Liu et al. extend those findings by showing that knockdown of NCAM decreased the abundance of NCAM180, NCAM140, and NCAM120; reduced the proliferation of a cultured melanoma cell line; reduced colony growth in soft agar; promoted morphological changes and gene expression characteristic of differentiation to an epithelial phenotype; and reduced growth of xenografted melanoma tumors in mice. Silencing NCAM in the melanoma cell line decreased the abundance of phosphorylated (and inactivated) glycogen synthase kinase 3β (GSK-3β) and reduced the abundance of β-catenin and transcription of β-catenin–responsive target genes. Unexpectedly, the activity of various Wnt receptors appeared unchanged by NCAM knockdown. Overexpression of NCAM140 or NCAM180, but not NCAM120, enhanced the proliferation of the cultured melanoma cell line, and coexpression of a dominant-negative form of β-catenin abolished this enhanced proliferation. Overexpression of NCAM140 or NCAM180 increased the abundance of β-catenin and phosphorylated GSK-3β. The extracellular domain of NCAM interacts with the fibroblast growth factor receptor (FGFR), and pharmacological inhibition of FGFR activity prevented overexpressed NCAM140 or NCAM180 from increasing β-catenin abundance or promoting phosphorylation of GSK-3β. Coimmunoprecipitation experiments and immunofluorescence experiments suggested that FGFR, NCAM, GSK-3β, and β-catenin formed a complex. The authors propose that NCAM may contribute to cancer by activating β-catenin signaling through a noncanonical pathway independent of Wnt signaling.

R. Liu, Y. Shi, H. J. Yang, L. Wang, S. Zhang, Y. Y. Xia, J. L. J. Wong, Z. W. Feng, Neural cell adhesion molecule potentiates the growth of murine melanoma via β-catenin signaling by association with fibroblast growth factor receptor and glycogen synthase kinase-3β. J. Biol. Chem. 286, 26127–26137 (2011). [Abstract] [Full Text]